The invention relates to a novel composition, in particular a pharmaceutical composition, comprising a synergistic combination of at least one ligand having activity for nuclear receptors of VDR type and at least one specific retinoid, as well as to the use of this composition in the pharmaceutical or cosmetic field.
It is known that a ligand having activity for nuclear receptors of VDR (vitamin D3 receptor) type, such as 1xcex1,25-dihydroxyvitamin D3 or analogues thereof, inhibits the proliferation of keratinocytes. Thus, this type of compound is used to treat psoriasis. However, these compounds, such as 1xcex1,25-dihydroxyvitamin D3, have side-effects: hypercalcaemia or hypercalciuria, due to an increase in the level of calcium in the serum.
It is known that retinoic acid is a modulator (i.e. an inhibitor or, on the contrary, a stimulator, depending on the nature of the cells treated) of the differentiation and/or proliferation of many normal or transformed cell types. For example, it inhibits the differentiation of epithelial cells, such as epidermal keratinocytes, without being especially active on the proliferation of these cells. It also inhibits the proliferation of many transformed cells, such as melanoma cells.
It is known, in general, that all-trans retinoic acid acts on the differentiation and/or proliferation of cells by interacting with nuclear receptors or RARs (retinoic acid receptors) contained in the cell nucleus. Many synthetic structural analogues of all-trans retinoic acid or of 9-cis-retinoic acid, commonly known as xe2x80x9cretinoidsxe2x80x9d, have been described to date in the literature. There exists, at the present time, three identified subtypes of RAR receptors referred to respectively as RAR-xcex1, RAR-xcex2 and RAR-xcex3. After binding of the ligand (i.e. of the all-trans retinoic acid), these receptors interact with the promoter region of genes regulated by retinoic acid at the level of specific response elements (RARE).
Certain analogues may bind and activate a specific subtype of RAR (xcex1, xcex2 or xcex3) receptor. Other analogues, lastly, have no specific selective activity towards these various receptors. In this respect, and, for example, all-trans retinoic acid activates RARs (specific RAR agonist ligand), all subtypes being taken together, whereas 13-cis retinoic acid does not bind to the xcex1 or xcex3 receptors.
Some of these retinoids have already been combined with vitamin D derivatives. Thus, in patent application AU-A-37161/93, 9-cis- or 13-cis-retinoic acid is combined with vitamin D derivatives. However; these combinations prove to be relatively unsatisfactory, in particular in the treatment of psoriasis. The need to find specific combinations which are of noteworthy efficacy, in particular in the treatment of psoriasis, may thus be appreciated.
One of the aims of the present invention is thus to be able to make available a novel product which exhibits appreciable inhibition of cell proliferation, in particular of skin cells, and more particularly of keratinocytes, allowing this product to be used in the treatment of disorders associated with cell hyperproliferation, in particular dermatological disorders associated with cell hyperproliferation.
Another aim of the present invention is to be able to make available a medicinal product which reduces, or even does away altogether with, the side-effects of ligands having activity for nuclear receptors of VDR type.
The Applicant has just discovered that the combination, which is novel per se, and in particular as a medicinal product, of at least one ligand having activity for nuclear receptors of VDR type and a specific retinoid which is selective for RARxcex3 receptors relative to RARxcex1 receptors, makes it possible to inhibit the proliferation of keratinocytes in an entirely noteworthy manner. This result is all the more unexpected and surprising since these retinoids, when they are used alone, have no, or substantially no, intrinsic antiproliferative activity towards these same cells.
This discovery forms the basis of the present invention.
Given the noteworthy activities which this combination in accordance with the invention exhibits towards keratinocytes, it naturally finds a preferred application in the treatment of dermatological disorders associated with hyperproliferation of skin cells, and more particularly of keratinocytes.
Thus, in one of its first aspects, the subject of the present invention is a combination product consisting of the combination of at least one ligand having activity for nuclear receptors of VDR type and at least one retinoid which is selective for RARxcex3 receptors relative to RARxcex1 receptors.
In a general and qualitative manner, a given substance (or ligand) is said to be specific for a particular receptor when the said substance exhibits an affinity for the said particular receptor which is stronger than that which it exhibits elsewhere for the other receptors.
The dissociation constants are determined by means of tests which are standard to those skilled in the art. These tests are described in particular in the following references: (1) xe2x80x9cSelective Synthetic Ligands for Nuclear Retinoic Acid Receptor Subtypesxe2x80x9d in RETINOIDS, Progress in Research and Clinical Applications, Chapter 19 (pp 261-267), Marcel Dekker Inc., published by Maria A. Livrea and Lester Packer; (2) xe2x80x9cSynthetic Retinoids: Receptor Selectivity and Biological Activityxe2x80x9d in Pharmacol. Skin, Basle, Karger, 1993, Volume 5, pp. 117-127; (3) xe2x80x9cSelective Synthetic Ligands for Human Nuclear Retinoic Acid Receptorsxe2x80x9d in Skin Pharmacology, 1992, Vol. 5, pp. 57-65; (4) xe2x80x9cIdentification of Synthetic Retinoids with Selectivity for Human Nuclear Retinoic Acid Receptor-xcex3xe2x80x9d in Biochemical and Biophysical Research Communications, Vol. 186, No. 2, July 1992, pp. 977-983; (5) xe2x80x9cSelective High Affinity RAR-xcex1 or RAR-xcex2 Retinoic Acid Receptor Ligandsxe2x80x9d in Mol. Pharmacol., Vol. 40, pp. 556-562.
In an advantageous manner, the retinoids which are selective for the RARxcex3 receptors relative to the RARxcex1 receptors have an RARxcex1/RARxcex3 dissociation constant ratio greater than or equal to 8.
Among the retinoids which are selective for the RARxcex3 receptors relative to the RARxcex1 receptors, mention may be made in particular of 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthoic acid (RARxcex1/RARxcex3=8.5), 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid (RARxcex1/RARxcex3=84.4) and 2-hydroxy-4-[3-hydroxy-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid (RARxcex1/RARxcex3=36.6) or derivatives thereof.
In general, the weight ratio between at least one ligand having activity for nuclear receptors of VDR type and at least one retinoid which is selective for RARxcex3 receptors relative to RARxcex1 receptors is between 1/1000 and 1000/1. Preferably, this weight ratio is between 1/10 and 10/1.
The subject of the present invention is also a novel composition, in particular a pharmaceutical composition, characterized in that it comprises, in a physiologically acceptable support, a combination product as defined above.
The ligands having activity for the VDR receptor are used for the treatment of osteoporosis, and it may thus be envisaged to use this combination product according to the invention for the treatment of osteoporosis.
However, this combination product proves to be very advantageous for a treatment intended to inhibit cell proliferation, in particular the proliferation of skin cells, and more particularly of keratinocytes, in particular for the treatment of psoriasis.
The subject of the invention is thus the use of at least one retinoid which is selective for RARxcex3 receptors relative to RARxcex1 receptors, for the manufacture of a pharmaceutical composition intended to increase the inhibitory activity on cell proliferation, in particular on skin cells, more particularly on keratinocytes, due to at least one ligand having activity for the VDR receptor used, for the treatment of disorders associated with cell hyperproliferation, in particular dermatological disorders associated with hyperproliferation of skin cells.
Thus, in the context of this use according to the invention, the retinoid may be administered, in a simultaneous manner or otherwise, via identical or different routes to the administration of the ligand having activity for the VDR receptor.
The present invention thus also relates to a product comprising at least one ligand having activity for nuclear receptors of VDR type and at least one retinoid which is selective for RARxcex3 receptors relative to RARxcex1 receptors, as a combination product for simultaneous or separate use or use spread out over time, for the treatment of disorders associated with cell hyperproliferation, in particular dermatological disorders associated with hyperproliferation of skin cells, more particularly of keratinocytes.
In the case where the retinoid is administered simultaneously and thus via an identical route to that of administration of the ligand having activity for the VDR receptor, the subject of the invention, lastly, is the use of the above combination product for the manufacture of a pharmaceutical composition, more particularly a dermatological composition, intended to treat disorders associated with cell hyperproliferation, in particular dermatological disorders associated with hyperproliferation of skin cells, and more particularly of keratinocytes. This composition is more particularly intended for the treatment of psoriasis.
The term skin cells is understood to refer to keratinocytes, melanocytes, fibroblasts, Merkel cells and Langerhans cells.
It will be noted in general that the active doses to be used in order to obtain the desired effect may be low, which constitutes an appreciable advantage when dealing with problems of undesirable side-effects liable to arise in the organisms to be treated or in the course of treatment, such as hypercalcaemia or hypercalciuria.
Other characteristics, aspects, objects and advantages of the invention will become even more clearly apparent on reading the description and the figures which follow, as well as the various specific, but in no way limiting, examples intended to illustrate it.